Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene and insufficient levels of its translated product, the SMN protein. SMA is the most common genetic cause of childhood mortality. Hallmarks of the disease in SMA mice and human patients include spinal motor neuron loss and skeletal muscle atrophy. Based on these characteristics it is widely believed that motor neurons are selectively vulnerable to reduced SMN and that muscle atrophy is a secondary consequence of neurodegeneration. These long-held beliefs notwithstanding, there continues to be a vigorous debate about whether motor neurons are indeed uniquely susceptible to reduced levels of SMN acting cell autonomously within them. Alternatively, neurodegeneration could be triggered by primary effects on some other cell type closely associated with motor neurons. If SMN does function within motor neurons to ensure their health and survival, it is not clear why they and not other cells are so sensitive to reduced levels of the protein. To better understand the molecular and cellular causes of SMA, mouse models that genetically mimic the human condition have been generated. In this application for funding to the NIH, we have outlined experiments described in three related aims to determine if SMA is a disease dictated exclusively by the health of the motor neurons and whether restoring normal levels of the SMN protein to this cell type is sufficient to completely ameliorate the disease phenotype. We propose to answer this question in two ways. Firstly, we will restore SMN selectively to the motor neurons of mice with SMA and ask if this results in complete phenotypic correction. Secondly, we will selectively deplete the SMN protein in the motor neurons and two associated tissues, muscle and glia, of healthy mice and ask to what extent such manipulations create neuromuscular pathology. In a second set of experiments, we will determine why insufficient SMN protein causes a selective degeneration of the neuromuscular system. To answer this question, we will look at the effects of reduced SMN on the development of the nerve-muscle synapse of SMA mice. If reduced SMN disrupts the development of this synapse and its constituent proteins which are crucial in ensuring proper nerve-muscle function, it will explain the neuromuscular pathology so characteristic of the human disease. Given the high frequency of SMA among humans, the lack of an effective treatment and the consequent burden it places on society, it is imperative that questions such as those posed here be answered in as timely a manner as possible. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy is a devastating neurodegenerative disease and the leading genetic killer of infants and toddlers. SMA is not presently treatable. Understanding why SMA results in neuromuscular failure and death is important to designing an appropriate treatment. In this proposal, we will use mouse models of the human condition to determine which cell types contribute to neuromuscular failure and why they degenerate. We believe our results will profoundly impact the design of successful therapies for SMA.